O-09: DURABLE ENGRAFTMENT AFTER PHARMACOLOGICAL PRE-TRANSPLANT IMMUNOSUPPRESSION FOLLOWED BY REDUCED-TOXICITY MYELOABLATIVE HAPLOIDENTICAL STEM CELL TRANSPLANTATION IN HIGHLY HLA-IMMUNIZED ADULTS WITH SICKLE CELL DISEASE
Authors: FÜRST S., BERNIT E., GRANATA A., LEGRAND F., HARBI S., DEVILLIER R., MAISANO V., BOUCHACOURT B., PAGLIARDINI T., MOKART D., LEMARIÉ C., CALMELS B., PICARD C., BASIRE A., CHABANNON C., ANDERSSON B., BLAISE D.
Journal: HemaSphere (2022)

Purpose: Sickle cell disease (SCD) is the most common genetic disorder worldwide and despite advances in best supportive care, remains a disease with high morbidity and mortality. Allogeneic stem cell transplantation (AlloHSCT) is a curative treatment modality. Reports in adults are limited because of the high risk of transplant related toxicity, graft rejection and the lack of suitable donors. The development of reduced-toxicity myeloablative conditioning (RT-MAC) regimen and the use of partially matched family donors with post-transplantation cyclophosphamide (PT-Cy) have widened the access to AlloHSCT. Antibodies against donor-specific HLA (DSA) which are frequently detected in multi-transfused SCD patients increase the risk of engraftment failure in HLA mismatched AlloHSCT. Materials and methods: We report the results of five patients with severe SCD (22, 46, 27, 30 and 30 years old) and DSA who underwent an unmanipulated haploidentical bone marrow transplantation (HaploBMT) after a RT-MAC regimen. The conditioning regimen consisted in rabbit antithymoglobuline (ATG), fludarabine (flu) and busulfan. GVHD prophylaxis was performed with PT-Cy, cyclosporine A and mycophenolate mofetil. To reduce the risk of engraftment failure, a sequential two courses pharmacological pre-transplant immunosuppression (PTIS) phase was added prior to the conditioning regimen. This initially was based on flu in combination with dexamethasone and was later modified to include cyclophosphamide (cy) and ATG in patients with CNS involvement. The desensitization protocol of DSA consisted in rituximab, velcade and plasmapheresis followed by high dose intravenous immunoglobulins. (Figure 1) Importantly, the patients were highly immunized with severe hemolytic crises and high DSA titers (range, MFI 2000 – 10003); two patients had also a history of cerebrovascular complications whereas the 46 years old woman with sickle cell specific multi-organ damage. All donors were first degree family members (sibling, parent, child). Results: All patients successfully engrafted with neutrophil reconstitution on days 26, 31, 16, 24 and 21 days (median 23 days), respectively. The procedure was well tolerated with only mild toxicity. None of the patients developed acute GVHD. One patient developed moderate chronic skin GVHD at day +489 after HaploBMT with rapid response to conventional immunosuppressive therapy. After a follow-up of 2323, 1770, 994, 962 and 263 days (median 994 days) respectively, chimerism analysis and detection of hemoglobin S confirmed sustained donor engraftment. All patients were free of any pain symptoms with excellent quality of life. Conclusion: Our report shows that HaploHSCT after a busulfan-based RT-MAC regimen is feasible and safe and allows stable long-term engraftment and excellent disease control. Graft failure may be overcome by adding a PTIS phase prior to the conditioning regimen. Further studies are necessary to confirm these promising results and allow a widened access of this platform technology to patients with high-risk sickle cell disease.Desensitization procedure E. BERNIT declares a conflict of interest: Consultancy, Expert: NOVARTIS PHARMA